Process and intermediates for preparing benzazepines

ABSTRACT

Disclosed is a new process and intermediates for preparing benzazepines of Formula (I): 
                         
wherein R 1  and R 2  are as defined herein.

This application is a 371 of International Application No.PCT/US2004/009909, filed 29 Mar. 2004.

FIELD OF THE INVENTION

This invention relates to processes and intermediates for preparingbenzazepine compounds that function as vitronectin receptor inhibitors.

BACKGROUND OF THE INVENTION

Integrins are a superfamily of cell adhesion receptors, which aretransmembrane glycoproteins expressed on a variety of cells. These cellsurface adhesion receptors include gpIIb/IIIa (the fibrinogen receptor)and α_(v)β₃ (the vitronectin receptor). The fibrinogen receptorgpIIb/IIIa is expressed on the platelet surface, and mediates. Thevitronectin receptor is known to refer to three different integrins,designated α_(v)β₁, α_(v)β₃ and α_(v)β₅ Compounds that inhibit theactivity of these receptors and associated integrins may be useful forthe treatment of inflammation, cancer and cardiovascular disorders, suchas atherosclerosis and restenosis, and diseases wherein bone resorptionis a factor, such as osteoporosis. Benzazepine compounds that are potentinhibitors of the α_(v)β₃ and α_(v)β₅ receptors are described in U.S.Pat. Nos. 5,939,412 and 6,127,359.

Each of the above publications describes a variety of procedures forconstructing benzazepines, however these processes employ expensivereagents and generally require a large number of steps in the syntheticsequence. Accordingly, it would be useful to develop an efficient andcost-effective process for the preparation of benzazepine compounds.

SUMMARY OF THE INVENTION

This invention is directed to a process for preparing a benzazepine ofFormula (I):

from a benzazepine-phenol of Formula (II):

wherein the benzazepine-phenol of Formula (II) is prepared by a processcomprising converting a compound of Formula (III):

to a compound of Formula (IV):

wherein R^(P), R¹, R², R³ and R⁴ are as defined herein.

This process further comprises converting the compound of Formula (IV)to the compound of Formula (II).

Another aspect of this invention relates to a process for thestereospecific preparation of a benzazepine of Formula (I-S):

from a benzazepine-phenol of Formula (II-S):

wherein the benzazepine-phenol of Formula (II-S) is prepared by aprocess comprising converting a compound of Formula (III):

to a compound of Formula (IV-S):

This process further comprises converting the compound of Formula (IV-S)to the compound of Formula (II-S).

Another aspect of this invention is a process for the preparation ofeach of8-[2-[6-(methylamino)pyridin-2-yl]-1-ethoxy]-3-oxo-2-(2,2,2-trifluoroethyl)-1,2,4,5-tetrahydro-2-benzazepine-4-aceticacid,S-(−)-8-[2-[6(methylamino)pyridin-2-yl]-1-ethoxy]-3-oxo-2-(2,2,2-trifluoroethyl)-1,2,4,5-tetrahydro-2-benzazepine-4-aceticacid,2,3,4,5-tetrahydro-3-oxo-8-[3-(2-pyridinylamino)propoxy]-2-(2,2,2-trifluoroethyl)-1H-2-benzazepine-4-aceticacid, and(S)-2,3,4,5-tetrahydro-3-oxo-8-[3-(2-pyridinylamino)propoxy]-2-(2,2,2-trifluoroethyl)-1H-2-benzazepine-4-aceticacid. Yet another aspect of this invention includes each of thecompounds: methyl2,3,4,5-tetrahydro-8-hydroxy-3-oxo-2-(2,2,2-trifluoroethyl)-1H-2-benzazepineacetate,(S)-methyl2,3,4,5-tetrahydro-8-hydroxy-3-oxo-2-(2,2,2-trifluoroethyl)-1H-2-benzazepine-4-acetate,2-[(2-formyl-4-hydroxyphenyl)methylidene]succinic acid,2-carboxyl-4-[(2-formyldimethylacetal-4-hydroxyphenyl)]butyric acid,bis(dicyclohexylamine) salt,(S)-2-carboxyl-4[(2-formyldimethylacetal-4-hydroxyphenyl)]butyric acid,bis(dicyclohexylamine) salt, dimethyl2-[(2-formylhydroxyphenyl)methyl]butanedioate, and dimethyl(2S)-2-[(2-formyl-4-hydroxyphenyl)methyl]butanedioate, and the processfor the preparation thereof.

DETAILED DESCRIPTION OF THE INVENTION

Benzazepine compounds that may be prepared by the processes of thisinvention include the compounds of Formula (I) and Formula (I-S):

wherein:

R² is R⁷, C₁-C₄ alkyl, C₁-C₄ haloalkyl, A-C₀-C₄ alkyl-, A-C₂-C₄alkenyl-, A-C₂-C₄ alkynyl-, A-C₃-C₄ oxoalkenyl-, A-C₃-C₄ oxoalkynyl-,A-C₀-C₄ aminoalkyl-, A-C₃-C₄ aminoalkenyl-, A-C₃-C₄ aminoalkynyl-,optionally substituted by any accessible combination of one or more ofR¹⁰ or R⁷;

A is H, C₃-C₆ cycloalkyl, Het or Ar;

R⁷ is —COR⁸, —COCR′₂R⁹, —C(S)R⁸, —S(O)_(m)OR′, —S(O)_(m)NR′R″, —PO(OR′),—PO(OR′)₂, —NO₂, or tetrazolyl;

each R⁸ independently is —OR′, —NR′R″, —NR′SO₂R′, —NR′OR′, or—OCR′₂CO(O)R′;

R⁹ is —OR′, —CN, —S(O)_(r)R′, —S(O)_(m)NR′₂, —C(O)R′, C(O)NR′₂, or—CO₂R′;

R¹⁰ is H, halo, —OR¹¹, —CN, —NR′R¹¹, —NO₂, —CF₃, CF₃S(O)_(r)—, —CO₂R′,—CONR′₂, A-C₀-C₆ alkyl-, A-C₁-C₆ oxoalkyl-, A-C₂-C₆ alkenyl-, A-C₂-C₆alkynyl-, A-C₀-C₆ alkyloxy-, A-C₀-C₆ alkylamino- or A-C₀-C₆alkyl-S(O)_(r)—;

R¹¹ is R′, —C(O)R′, —C(O)NR′₂, —C(O)OR′, —S(O)_(m)R′, or —S(O)_(m)NR′₂;

R¹ is

W is —(CHR^(g))_(a)—U—(CHR^(g))_(b)—;

U is absent or CO, CR^(g) ₂, C(═CR^(g) ₂), S(O)_(k), O, NR^(g),CR^(g)OR^(g), CR^(g)(OR^(k))CR^(g) ₂, CR^(g) ₂CR^(g)(OR^(k)), C(O)CR^(g)₂, CR^(g) ₂C(O), CONR^(i), NR^(i)CO, OC(O), C(O)O, C(S)O, OC(S),C(S)NR^(g), NR^(g)C(S), S(O)₂NR^(g), NR^(g)S(O)₂N═N, NR^(g)NR^(g),NR^(g)CR^(g) ₂, CR^(g) ₂NR^(g), CR^(g) ₂O, OCR^(g) ₂, C≡C orCR^(g)═CR^(g);

G is NR^(e), S or O;

R^(g) is H, C₁-C₆ alkyl, Het-C₀-C₆ alkyl, C₃-C₇ cycloalkyl-C₀-C₆ alkylor Ar—C₀-C₆ alkyl;

R^(k) is R^(g), —C(O)R^(g), or —C(O)OR^(f);

R^(i) is H, C₁-C₆ alkyl, Het-C₀-C₆ alkyl, C₃-C₇ cycloalkyl-C₀-C₆ alkyl,Ar—C₀-C₆ alkyl, or C₁-C₆ alkyl substituted by one to three groups chosenfrom halogen, CN, NR^(g) ₂, OR^(g), SR^(g), CO₂R^(g), and CON(R^(g))₂;

R^(g) is H, C₁-C₆ alkyl or Ar—C₀-C₆ alkyl;

R^(e) is H, C₁-C₆ alkyl, Ar—C₀-C₆ alkyl, Het-C₀-C₆ alkyl, C₃-C₇cycloalkyl-C₀-C₆ alkyl, or (CH₂)_(k)CO₂R^(g);

R^(b) and R^(c) are independently selected from H, C₁-C₆ alkyl, Ar—C₀-C₆alkyl, Het-C₀-C₆ alkyl, or C₃-C₆ cycloalkyl-C₀-C₆ alkyl, halogen, CF₃,OR^(f), S(O)_(k)R^(f), COR^(f), NO₂, N(R^(f))₂, CO(NR^(f))₂,CH₂N(R^(f))₂, or R^(b) and R^(c) are joined together to form a five orsix membered aromatic or non-aromatic carbocyclic or heterocyclic ring,optionally substituted by up to three substituents chosen from halogen,CF₃, C₁-C₄ alkyl, OR^(f), S(O)_(k)R^(f), COR^(f), CO₂R^(f), OH, NO₂,N(R^(f))₂, CO(NR^(f))₂, and CH₂N(R^(f))₂; or methylenedioxy;

Q¹, Q², Q³ and Q⁴ are independently N or C—R^(y), provided that no morethan one of Q¹, Q², Q³ and Q⁴is N;

R′ is H, C₁-C₆ alkyl, Ar—C₀-C₆ alkyl or C₃-C₆ cycloalkyl-C₀-C₆ alkyl;

R″ is R′, —C(O)R′ or —C(O)OR′;

R′″ is H, C₁-C₆ alkyl, Ar—C₀-C₆ alkyl, Het-C₀-C₆ alkyl, or C₃-C₆cycloalkyl-C₀-C₆ alkyl, halogen, CF₃, OR^(f), S(O)_(k)R^(f), COR^(f),NO₂, N(R^(f))₂, CO(NR^(f))₂, CH₂N(R^(f))₂;

R^(y) is H, halo, —OR^(g), —SR^(g), —CN, —NR^(g)R^(k), —NO₂, —CF₃,CF₃S(O)_(r)—, —CO₂R^(g), —COR^(g) or —CONR^(g) ₂, or C₁-C₆ alkyloptionally substituted by halo, —OR^(g), —SR⁹, —CN, —NR^(g)R″, —NO₂,—CF₃, R′S(O)_(r)—, —CO₂R^(g), —COR^(g) or —CONR^(g) ₂;

a is 0, 1 or 2;

b is 0, 1 or 2;

k is 0, 1 or 2;

m is 1 or 2;

r is 0, 1 or 2;

s is 0, 1 or 2;

u is 0 or 1; and

v is 0 or 1;

or a pharmaceutically acceptable salt thereof.

As used herein, C₁-C₄ alkyl as applied herein means an optionallysubstituted alkyl group of 1 to 4 carbon atoms, and includes methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl. C₁-C₆ Alkyladditionally includes pentyl, n-pentyl, isopentyl, neopentyl and hexyland the simple aliphatic isomers thereof. C₀-C₄ Alkyl and C₀-C₆ alkyladditionally indicates that no alkyl group need be present (e.g., that acovalent bond is present).

Any C₁-C₄ alkyl or C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl or C₁-C₆oxoalkyl may be optionally substituted with the group R^(x), which maybe on any carbon atom that results in a stable structure and isavailable by conventional synthetic techniques. Suitable groups forR^(x) are C₁-C₄ alkyl, OR′, SR′, C₁-C₄ alkylsulfonyl, C₁-C₄alkylsulfoxyl, —CN, N(R′)₂, CH₂N(R′)₂, —NO₂, —CF₃, —CO₂R′—CON(R′)₂,—COR′, —NR′C(O)R′, F, Cl, Br, I, or CF₃S(O)_(r)—, wherein r is 0, 1 or2.

Halogen or halo means F, Cl, Br, and I.

Ar, or aryl, as applied herein, means phenyl or naphthyl, or phenyl ornaphthyl substituted by one to three substituents, such as those definedabove for alkyl, especially C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ alkylthio,CF₃, NH₂, OH, F, Cl, Br or I.

Het, or heterocycle, indicates an optionally substituted five or sixmembered monocyclic ring, or a nine or ten-membered bicyclic ringcontaining one to three heteroatoms chosen from the group of nitrogen,oxygen and sulfur, which are stable and available by conventionalchemical synthesis. Illustrative heterocycles are benzofuryl,benzimidazolyl, benzopyranyl, benzothienyl, furanyl, imidazolyl,indolyl, morpholinyl, piperidinyl, piperazinyl, pyrrolyl, pyrrolidinyl,tetrahydropyridinyl, pyridinyl, thiazolyl, thienyl, quinolyl,isoquinolyl, and tetra- and perhydro-quinolyl and isoquinolyl. Anyaccessible combination of up to three substituents on the Het ring, suchas those defined above for alkyl that are available by chemicalsynthesis and are stable are within the scope of this invention.

C₃-C₇ Cycloalkyl refers to an optionally substituted carbocyclic systemof three to seven carbon atoms, which may contain up to two unsaturatedcarbon-carbon bonds. Typical of C₃-C₇ cycloalkyl are cyclopropyl,cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl andcycloheptyl. Any combination of up to three substituents, such as thosedefined above for alkyl, on the cycloalkyl ring that is available byconventional chemical synthesis and is stable, is within the scope ofthis invention.

When R^(b) and R^(c) are joined together to form a five- or six-memberedaromatic or non-aromatic carbocyclic or heterocyclic ring fused to thering to which R^(b) and R^(c) are attached, the ring formed willgenerally be a five- or six-membered heterocycle selected from thoselisted above for Het, or will be a phenyl, cyclohexyl or cyclopentylring. Preferably R^(b) and R^(c) will be −D1=D2-D3=D4 wherein D1-D4 areindependently CH, N or C—R^(x) with the proviso that no more than two ofD1-D4 are N. Most preferably, when R^(b) and R^(c) are joined togetherthey form the group —CH═CH—CH═CH—.

Compounds of Formula (I) may be prepared by a process comprisingconverting a compound of Formula (III):

to a compound of Formula (IV):

wherein R^(P) is H or a suitable phenol protecting group, R³ and R⁴ arethe same or different and are each independently H or a carboxylic acidester protecting group. As described herein, this conversion may beconducted by hydrogenation, specifically catalytic hydrogenation. Itwill be understood by those skilled in the art that different reactionconditions (hydrogen pressure, catalyst, temperature, solvent, etc.) maybe required to effect this conversion when different protecting groupsare used. Additionally, the use of different protecting groups canresult in different, often poorer, conversion yields. In anotherembodiment, each R³ and R⁴ may be independently H, C₁-C₆ alkyl or phenylC₁-C₄ alkyl- (e.g., benzyl) wherein the phenyl moiety may beunsubstituted or substituted by one or more substituents selected fromortho and para substituents selected from chloro, bromo, nitro, methoxyand methyl. In a specific embodiment, the process of this invention isconducted wherein R³ and R⁴ are each independently H or C₁-C₄ alkyl,specifically R³ is methyl and R⁴ is H. The term “R^(P)” is used hereinto denote H or a suitable protecting group for a phenolic functionalgroup. In one specific embodiment of this invention, R^(P) of compoundsIII, IV and IV-S is H.

Suitable protecting groups for phenols, amines, carboxylic acids,aldehydes, etc., and the methods for protecting and de-protecting suchsubstituents using such suitable protecting groups are well known tothose skilled in the art; examples of which may be found in T. Greeneand P. Wuts, Protecting Groups in Chemical Synthesis (3rd ed.), JohnWiley & Sons, NY (1999). For example, suitable phenol protecting groupsinclude benzyloxycarbonyl, benzyl, and the like. Substitution of thebenzyloxycarbonyl or benzyl protecting groups can be used to modify thereactivity of the protective group. Suitable substitution of the phenylring moiety of the benzyloxycarbonyl or benzyl group is ortho and/orpara substitution with chloro, bromo, nitro, methoxy or methyl. Suitableamine protecting groups include benzyl, Boc, Cbz, phthaloyl, Fmoc andthe like. Suitable carboxylic acid ester protecting groups (e.g., R³ orR⁴) include methyl, ethyl, t-Bu, cHex, benzyl, substituted benzyl,(pivaloyl)methyl or (2-methyl-2-methoxypropanoyl)methyl esters and thelike. Suitable aldehyde protecting groups (represented hereinbelow as—ZR⁵ and —Z′R^(5′)) include. acetals (cyclic acetals, non-cyclic acetals(e.g., di-alkyl acetals) and aminals.

Methods for removal of carboxy or amino protecting groups are well knownin the art. For example, an alkyl or cycloalkyl ester may be removed bybasic hydrolysis, for instance an alkali metal hydroxide, such assodium, potassium or lithium hydroxide in a suitable solvent, such asaqueous alcohol. A benzyl ester is typically removed by hydrogenationover a palladium catalyst. A basic nitrogen protected by atert-butyloxycarbonyl group, or a t-butyl ester, is typically removed byacid treatment, such as by trifluoroacetic acid or hydrochloric acid,optionally diluted with a solvent, such as methylene chloride and/ordioxane. The benzyloxycarbonyl group is generally removed byhydrogenation over a palladium catalyst. A trifluoroacetyl group istypically removed by basic hydrolysis, such as by treatment with analkali metal hydroxide in a suitable solvent.

In yet another specific embodiment of this invention, a compound ofFormula (I) may be prepared by a process which comprises converting acompound of Formula (III) to a compound of Formula (IV-S)

wherein R³ is as defined above.

According to the process of this invention, the compound of Formula(III) is converted to the compound of Formula (IV) via reduction of anintermediate compound of Formula (A) having the structure:

wherein R⁴ is as defined above and the moieties —ZR⁵ and —Z′R^(5′) takentogether constitute a protected aldehyde moiety (e.g., an acetal,aminal, etc.) wherein R⁵ and R^(5′) are C₁-C₄ alkyl or R⁵ and R^(5′),taken together with the atoms to which they are attached form asaturated 5- or 6-membered heterocyclic ring and Z and Z′ areindependently selected from O, NH or NCH₃. In one embodiment, theprocess of this invention is conducted wherein Z and Z are both O. Inanother embodiment, the process of this invention is conducted whereinR⁵ and R^(5′) are each C₁-C₄ alkyl, specifically methyl, R^(p) is H andeach R⁴ is H.

The intermediate compound of Formula (A), where each R⁴ is H. may becrystallized from the reaction mixture, specifically as a base salt.Examples of base salts of the intermediate compound of Formula (A)include the di-alkaline metal hydroxide salts (such as the di-sodiumhydroxide salt, the di-potassium hydroxide salt or the di-lithiumhydroxide salt) or bis-amine salts, wherein any basic mono-, di- ortri-substituted alkyl or aryl amine, or diamine (such as ethylenediamine) may be used to form the bis-salt. Useful amines includedicyclohexylamine and tert-butyl amine. In one embodiment, the compoundof Formula (A) was preferably isolated as a bis(dicyclohexylamine salt).

A compound of Formula (III) is converted to a compound of Formula (A),bearing a protected aldehyde moiety using conventional procedures. Thealdehyde protecting group may be removed at a suitable point in thereaction sequence of the process of this invention to provide a desiredintermediate or target compound. Preferably, the aldehyde protectinggroups is removed after hydrogenation of the compound of Formula (A).

Reduction of a compound of Formula (A), by hydrogenation using apalladium catalyst (e.g., palladium on carbon) results in the formationo f a compound of Formula (B):

wherein Z, Z′, R⁴, R⁵, and R^(5′) are as defined above. Preferredvitronectin inhibitor compounds of Formula (I) have been identified aspossessing an absolute configuration of (S) at the 4-position of thebenzazepine. Accordingly, a preferred embodiment of the process of thisinvention comprises conducting the reduction of a compound of Formula(A) of this invention by hydrogenation using an optically activehydrogenation catalyst or by using components that form an opticallyactive hydrogenation catalyst in situ to form a compound of Formula(B-S), substantially as (S) enantiomer:

Asymmetric hydrogenation catalysts that may be used to providesubstantially the (S)-isomer of Compound (B-S), and thereby Compounds(I-S), (II-S), (IV-S) are known in the art. See for example, U.S. Pat.No. 4,939,288, T. Morimoto, et al., Tetrahedron Letters, Vol. 30, No. 6,735-738 (1989) and J. D. White, et al., J. Org. Chem., Vol. 62,5250-5251 (1997). Suitable hydrogenation catalysts include[Rh(COD)Cl]₂—(S,S)-DIOP, [Rh(NBD)]₂ClO₄-JOSIPHOS,[(R,R-DIPAMP)Rh(COD)]BF₄, [(S,S-DiethylDUPHOS)Rh]SO₃CF₃, and[Ru(S-BINAP)Cl]₂-TEA (with or without additional TEA). Preferably, thehydrogenation catalyst is [Ru(S-BINAP)Cl]₂-TEA (without added TEA).Preferably, the asymmetric hydrogenation is conducted in the presence ofa mono-, di- or tri-substituted amine base. It will be understood bythose skilled in the art that the use of different amine bases (e.g.,tert-butyl amine or triethylamine or di-cyclohexylamine) will providedifferent reaction outcomes (% conversion/yield and % enantiomericexcess) when different protecting groups are used. The identification ofpreferred and/or optimal protecting group/amine base combinations isconsidered to be a matter of routine experimentation for one of ordinaryskill in the art.

One embodiment of this invention relates to a process for thepreparation of a compound of Formula (II), comprising the steps of:

-   1) treating a compound having Formula (a)

wherein R^(P) is H or a suitable phenol protecting group and X ishalogen, —OSO₂F, or —OSO₂CF₃, with a compound having the Formula:

to form a compound of Formula (b)

-   2) converting the compound of Formula (b) to a compound of Formula    (c);

wherein Z, Z′, R⁵ and R^(5′) are identified above,

-   3) converting the compound of Formula (c) to a compound of Formula    (d):

-   4) converting the compound of Formula (d) to a compound of Formula    (e)

-   5) converting the compound of Formula (e) to a compound of Formula    (f)

-   6) converting the compound of Formula (f) to a compound of Formula    (II).

In one embodiment of the process of this invention, R³ and R⁴ are eachindependently H or C₁-C₄ alkyl (more specifically, R³ is methyl and R⁴is H), R^(P) is H, X is a halogen, Z and Z′ are O and R⁵ and R^(5′) areC₁-C₄ alkyl.

Another embodiment of this invention relates to a process for thepreparation of a compound of Formula II, comprising the steps of:

-   1) converting 3-hydroxybenzaldehyde to a compound of Formula (aa)

-   2) treating the compound of Formula (aa) with itaconic acid to form    a compound of Formula (bb):

-   3) converting the compound of Formula (bb) to a compound of Formula    (cc)

-   4) converting the compound of Formula (cc) to a compound of Formula    (dd)

-   5) converting the compound of Formula (dd) to a compound of Formula    (ee)

-   6) converting the compound of Formula (ee) to the compound of    Formula (II).

In a specific embodiment of the process of this invention describedabove, R³ and R⁴ are each independently H or C₁-C₄ alkyl (morespecifically, R³ is methyl and R⁴ is H), R^(P) is H, and R⁵ and R^(5′)are methyl.

Another embodiment of this invention relates to a process for thepreparation of a compound of Formula (II) comprising the steps of:

-   1) converting a compound having Formula (a)

wherein R^(P) is H or a suitable phenol protecting group and X ishalogen, —OSO₂F, or —OSO₂CF₃, to a compound of Formula (a′)

wherein —ZR⁵ and —Z′R^(5′) are as defined hereinabove;

-   2) treating the compound of Formula (a′) with a compound having the    Formula:

to form a compound of Formula (c′)

-   3) converting the compound of Formula (b′) to a compound of Formula    (c);

-   4) converting the compound of Formula (c) to a compound of Formula    (d)

-   5) converting the compound of Formula (d) to a compound of Formula    (e)

-   6) converting the compound of Formula (e) to a compound of Formula    (f)

-   7) converting the compound of Formula (f) to the compound of Formula    (II).

In one embodiment of the process of this invention described above, R³and R⁴ are each independently H or C₁-C₄ alkyl (more specifically, R³ ismethyl and R⁴ is H), R^(P) is H, X is a halogen, Z and Z′ are O and R⁵and R^(5′) are C₁-C₄ alkyl.

Another embodiment of this invention relates to a process for thepreparation of a compound of Formula (II) comprising the steps of:

-   1) converting 2-bromo-5-hydroxy-benzaldehyde to a compound of    Formula (h)

-   2) treating the compound of Formula (h) with itaconic acid to form a    compound of Formula (i)

-   3) converting the compound of Formula (i) to a compound of Formula    (j);

-   4) converting the compound of Formula (j) to a compound of Formula    (k)

-   5) converting the compound of Formula (k) to a compound of Formula    (l)

-   6) converting the compound of Formula (l) to the compound of Formula    (II).

In a specific embodiment of the process of this invention describedabove, R³ is methyl, R^(P) is H, and R⁵ and R^(5′) are methyl.

Accordingly, in another embodiment of this invention, the process forthe preparation of a compound of Formula (II-S) comprising the steps of:

-   1) converting the compound having the formula:

to a compound having the formula:

-   2) converting the compound formed in step 1) into a compound having    the formula:

-   3) converting the compound formed in step 2) into the compound    having the formula:

-   4) converting the compound formed in step 3) into the compound of    Formula (II-S).

More specifically, a process for the preparation of a compound ofFormula (II-S) comprising the steps of:

-   1) converting the compound having the formula:

into a compound having the formula:

-   2) converting the compound formed in step 1) into a compound having    the formula:

-   3) converting the compound formed in step 2) into the compound of    Formula (II-S).

Another embodiment of this invention relates to a process for thepreparation of a compound of Formula I, having the formula:

comprising the steps of:

-   1) converting 2-amino-6-methylpyridine into a compound having the    Formula:

wherein R^(P) is a suitable amino protecting group,

-   2) converting the compound formed in step 1) to a compound having    the formula:

-   3) converting the compound formed in step 2) to a compound having    the formula:

wherein R⁶ is H or a suitable alkyl carboxylic acid ester (e.g., acetyl)protecting group;

-   4) converting the compound formed in step 3) to a compound having    the formula:

-   5) treating the compound formed in step 4) with a compound having    the formula:

to form a compound having the formula:

-   6) converting the compound formed in step 5) to the compound of    Formula I.

In one embodiment of the process of this invention described above,R^(P) is tert-butoxycarbonyl, R³ is H or C₁-C₄ alkyl (more specifically,R³ is methyl), and R⁶ is C₁-C₄ alkyl.

One embodiment of this invention relates to a process for thepreparation of a compound of Formula (I), having the formula:

comprising the steps of:

-   1) converting 2-amino-6-methylpyridine into a compound having the    Formula:

-   2) converting the compound formed in step 1) to a compound having    the formula:

-   3) converting the compound formed in step 2) to a compound having    the formula:

-   4) converting the compound formed in step 3) to a compound having    the formula:

-   5) treating the compound formed in step 4) with a compound having    the formula:

to form a compound having the formula:

-   6) converting the compound formed in step 5) to the compound of    Formula (I).

Another embodiment of this invention relates to a process for thepreparation of a compound of Formula (I) having the formula:

comprising the steps of:

-   1) converting a compound having Formula (a)

wherein X is halogen or —OSO₂CF₃,to a compound of Formula (b)

-   2) converting the compound formed in step 1) into a compound having    the Formula:

wherein X′ is halogen, —OSO₂CH₃, —OSO₂CF₃, —OSO₂(phenyl), or—OSO₂(p-tolyl);

-   3) treating the compound formed in step 2) with a compound having    the Formula:

to form a compound having the formula:

-   4) converting the compound formed in step 3) into the compound of    Formula (I).

In one embodiment of the process of this invention described above, Xand X′ are each halogen and R³ is C₁-C₄ alkyl, more specifically, X andX′ are each bromo and R³ is methyl.

Another embodiment of this invention relates to a process for thepreparation of a compound of Formula (I) having the formula:

comprising the steps of:

-   1) converting 2-chloropyrdine, N-oxide to a compound of Formula (b)

-   2) converting the compound formed in step 1) into a compound having    the Formula:

-   3) treating the compound formed in step 2) with a compound having    the Formula:

to form a compound having the formula:

-   4) converting the compound formed in step 3) into the compound of    Formula (I).

In another embodiment of this invention, the process for the preparationof a compound of Formula (II):

comprising the step of treating the compound having the formula:

with a compound having the formula:

wherein R² and R⁴ are as defined herein.

More specifically, a process for the preparation of the compound havingthe formula:

comprising the step of treating the compound having the formula:

with a compound having the formula:

Another embodiment of this invention relates to a process for thepreparation of a compound of Formula (I) having the formula:

comprising the step of treating the compound having the Formula:

with a compound having the Formula:

Yet another embodiment of this invention relates to a process for thepreparation of a compound having the formula:

comprising the step of treating the compound having the Formula:

with a compound having the Formula:

The following compound is useful in the preparation of the compounds ofFormula (I) and particularly, the compounds of Formula (I-S):

wherein R^(P), R⁴, R⁵, R^(5′), Z and Z′ are as defined above, or apharmaceutically acceptable salt or solvate thereof. In a moreparticular embodiments of the above compound of this invention, R⁴ is H,C₁-C₆ alkyl or phenyl-C₁-C₄ alkyl-, wherein the phenyl moiety isunsubstituted or substituted by one or more substituents selected fromortho and para substituents selected from chloro, bromo, nitro, methoxyand methyl. More specifically, R⁴ is H or C₁-C₄ alkyl, or even morespecifically, R⁴ is H. In other more specific embodiments, R^(P) is H orZ and Z′ are both O or R⁵ and R^(5′) are C₁-C₄ alkyl. More specifically,R⁵ and R^(5′) are methyl.

The following compound is also useful in the preparation of thecompounds of Formula (I) and particularly, the compounds of Formula(I-S):

wherein R^(P), R³, R⁵, R^(5′), Z and Z′ are as defined above, or apharmaceutically acceptable salt or solvate thereof. In a moreparticular embodiments of the above compound of this invention, R³ is H,C₁-C₆ alkyl or phenyl-C₁-C₄ alkyl-, wherein the phenyl moiety isunsubstituted or substituted by one or more substituents selected fromortho and para substituents selected from chloro, bromo, nitro, methoxyand methyl. More specifically, R³ is H or C₁-C₄ alkyl. Even morespecifically, R³ is C₁-C₄ alkyl, specifically, methyl. In other morespecific embodiments, R^(P) is H or Z and Z′ are both O or R⁵ and R^(5′)are C₁-C₄ alkyl. More specifically, R⁵ and R^(5′) are methyl.General Methods

The following General Methods described in more detail the specificconversion steps of the above-described processes. Scheme 1 illustratesone embodiment of this invention for the preparation of a compound ofFormula (II).

Scheme 2 illustrates one embodiment of this invention for thepreparation of a compound of Formula (II).

In Schemes 1 and 2, and in the processes generically described above, a3-hydroxybenzaldehyde was brominated to provide2-bromo-5-methoxy-benzaldehyde. This compound may be protected as anacetal in situ, then reacted with itaconic acid under Heck conditionsand deprotected to provide 2-(2-formyl-4-hydroxy-benzylidene)-succinicacid. This compound was protected as an acetal and thenenantioselectively hydrogenated to provide(S)-2-[2-(1,1-dimethoxy-methyl)-4-hydroxy-benzyl]-succinic acid. Theasymmetric hydrogenation is preferably conducted in the presence of amono-, di- or tri-substituted amine. Advantageously, the hydrogenationcan be conduced in the presence of triethylamine or dicyclohexylamine,which provides the resulting succinic acid product as the correspondingbis-amine salt (e.g. as(S)-2-[2-(1,1-dimethoxy-methyl)-4-hydroxy-benzyl]-succinic acidbis-dicyclohexyl amine). The free acid was re-generated, the acetal wasconverted to an aldehyde, and the di-acid was esterified in one step toyield (S)-2-2-formyl-4-hydroxy-benzyl)-succinic acid dimethyl ester.Finally the resulting compound was reacted with2,2,2-trifluoroethylamine under reductive amination conditions and thencyclized under acidic catalysis to provide[(S)-8-hydroxy-3-oxo-2-(2,2,2-trifluoro-ethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-4-yl]-aceticacid methyl ester.

Another embodiment of this invention, illustrated in Scheme 3, comprisesa process for the preparation of a compound according to Formula(I) fromFormula(II). Generally, this process comprises converting abenzazepine-phenol compound of Formula (II) to a benzazepione-ethercompound of Formula (I) by introducing an R¹ substituent and hydrolyzingthe carboxylate at the 4-position of the benzazepine to thecorresponding acid. Suitable R¹ substituents are described in thepatents and patent applications provided herein.

An example of an improved processes for the preparation of8-[2-[6-(methylamino)pyridin-2-yl]-1ethoxy]-3-oxo-2-(2,2,2-trifluoroethyl)-1,2,4,5-tetrahydro-2-benzazepine-4-aceticacid, specifically,S-(−)-8-[2-[6-(methylamino)pyridin-2-yl]-1-ethoxy]-3-oxo-2-(2,2,2-trifluoroethyl)-1,2,4,5-tetrahydro-2-benzazepine-4-aceticacid using 6-(methylamino)-2-pyridineethanol is illustrated in Scheme 3.

S-(−)-8-[2-[6-(Methylamino)pyridin-2-yl]-1-ethoxy]-3-oxo-2-(2,2,2-trifluoroethyl)-1,2,4,5-tetrahydro-2-benzazepine-4-aceticacid may be prepared by a thirteen step convergent synthesis from 2 keyintermediates, the compound of Formula (II) or (II-S), described aboveand suitable R²-group precursor. One such suitable R²-group precursormay be prepared from 2-amino-6-methyl-pyridine as described herein. Theamino group of 2-amino-6-methyl-pyridine may be was protected using anysuitable protecting group. Preferably, 2-amino-6-methyl-pyridine wasprotected using a BOC protecting group to provide(6-methyl-pyridin-2-yl)-carbamic acid tert-butyl ester, which wasconverted to 1,1-dimethylethyl methyl(6-methyl-2-pyridinyl)carbamate.1,1-Dimethylethyl methyl(6-methyl-2-pyridinyl)carbamate was converted toa 6-[[(1,1-dimethylethoxy)carbonyl]methylamino]-2-pyridineacetate bytreatment with a base and a suitable carboxylating agent, where thecarboxyl group may optionally be protected to provide a6-[[(1,1-dimethylethoxy)carbonyl]methylamino]-2-pyridineacetate. In aspecific embodiment of this invention, 1,1-dimethylethylmethyl(6-methyl-2-pyridinyl)carbamate was converted to ethyl6-[[(1,1-dimethylethoxy)carbonyl]methylamino]-2-pyridineacetate bytreatment with LDA and diethyl carbonate. The carboxylate moiety of the6-[[(1,1-dimethylethoxy)carbonyl]methylamino]-2-pyridine acetate may bereduced using any suitable reducing agent to provide2-(6-methylamino-pyridin-2-yl)-ethanol, which is a suitable pyridylR²-group precursor compound. In a specific embodiment of this invention,the 6[[(1,1-dimethylethoxy)carbonyl]methylamino]-2-pyridine acetate wasreduced using lithium borohydride. Advantageously,2-(6-methylamino-pyridin-2-yl)-ethanol may be isolated as a formatesalt. The free amine may be re-generated by treatment with NaOH.

[(S)-8-Hydroxy-3-oxo-2-(2,2,2-trifluoro-ethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-4-yl]-aceticacid methyl ester and 2-(6methylamino-pyridin-2-yl)-ethanol may becoupled using a variety of conventional procedures, preferably using aMitsunobo reaction. However, coupling using Williamson ether or Buchwaldconditions provided low yields of coupled product or were notsuccessful. The product (containing a —CO₂R³ ester group of the compoundof Formula (II) or (II-S)) may be hydrolyzed in the same step to providecrudeS-(−)-8-[2-[6-(methylamino)pyridin-2-yl]-1-ethoxy]-3-oxo-2-(2,2,2-trifluoroethyl)-1,2,4,5-tetrahydro-2-benzazepine4aceticacid. The crude product is preferably recrystallized from methanol/waterand the solid heated in ethyl acetate to obtain a single polymorph.

An example of an improved processes for the preparation of2,3,4,5-tetrahydro-3-oxo-8-[3-(2-pyridinylamino)propoxy]-2-(2,2,2-trifluoroethyl)-1H-2-benzazepine-4-aceticacid, specifically,(S)-2,3,4,5-tetrahydro-3-oxo-8-[3-(2-pyridinylamino)propoxy]-2-(2,2,2-trifluoroethyl)-1H-2-benzazepine-4-aceticacid using 2-(3-bromopropyl)aminopyridine-N-oxide hydrobromide isillustrated in Scheme 4.

-   2-(3-Hydroxypropyl)aminopyridine-N-oxide may be obtained from    2-chloro-pyridine-N-oxide by treatment with sodium bicarbonate,    3-amino-1-propanol, and t-amyl alcohol. The hydroxyl moiety of    2-(3-hydroxypropyl)aminopyridine-N-oxide may be converted to a    suitable leaving group, such as a halide, a mesylate, triflate,    benzenesulfonate, etc., using conventional procedures. For example,    2-(3-hydroxypropyl)aminopyridine-N-oxide may be converted to the    corresponding bromide by treatment with thionyl bromide or by    treatment with hydrobromic acid and acetic acid.    2-(3-Bromopropyl)aminopyridine-N-oxide (as the hydrobromide salt)    and    [(S)-8-hydroxy-3-oxo-2-(2,2,2-trifluoro-ethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-4-yl]-acetic    acid methyl ester may be coupled using a base, for example sodium    hydroxide. Reduction of the pyridyl N-oxide may be accomplished    under conventional conditions, more specifically, by treatment with    zinc dust in methanol. Hydrolysis of the methyl or ethyl ester    moiety (e.g., the —CO₂R³ ester group of the compound of Formula (II)    or (II-S)) was accomplished by treatment with aqueous base (NaOH).    The product may be recrystallized from methanol/methyl t-butyl ether    and hexane.

Abbreviations and symbols commonly used in the chemical arts are usedherein to describe the compounds, reactions and reagents of thisinvention.

Certain radical groups may be abbreviated herein. The followingdefinitions apply to the abbreviated radical groups: t-Bu refers to thetertiary butyl radical, Boc refers to the t-butyloxycarbonyl radical, Phrefers to the phenyl radical, CBZ refers to the benzyloxycarbonylradical, Bn refers to the benzyl radical, Me refers to methyl, Et refersto ethyl, and Ac refers to acetyl.

The simple starting materials for preparing the compounds of thisinvention are commercially available or prepared by routine methods wellknown in the art.

The intermediate compounds of this invention are useful as intermediatesin the preparation of pharmaceutically active compounds, in particularcompounds which have fibrinogen and vitronectin antagonist properties.

EXAMPLES

Nuclear magnetic resonance spectra were recorded at 270 MHz. CDCl₃ isdeuteriochloroform, DMSO-d₆ is hexadeuteriodimethylsulfoxide, and CD₃ODis tetradeuteriomethanol. Chemical shifts are reported in parts permillion (δ) downfield from the internal standard tetramethylsilane.Abbreviations for NMR data are as follows: s=singlet, d=doublet,t=triplet, q=quartet, m=multiplet, dd=doublet of doublets, dt=doublet oftriplets, app=apparent, br=broad. J indicates the NMR coupling constantmeasured in Hertz. HRMS indicates high resolution mass spectroscopy.Other abbreviations used herein include: EtOAc refers to ethyl acetate,MeOH refers to methanol, TFA refers to trifluoroacetic acid, THF refersto tetrahydrofuran, TBME refers to tert-butyl-methyl ether, Et₃N or TEArefers to triethylamine, DCA refers to dicyclohexylamine, LDA refers tolithium diisopropyl amine, DCC refers to dicyclohexylcarbodiimide, DMAPrefers to dimethylaminopyridine, DIEA refers to diisopropylethylamine,DMF refers to dimethyl formamide, and Pd—C refers to a palladium oncarbon catalyst.

Example 1 6-Bromo-3-hydroxybenzaldehyde

3-Hydroxybenzaldehyde (120 g, 0.98 moles) was suspended in 2400 mL ofCH₂Cl₂ in a 5 L 4-neck round bottom flask equipped with overheadstirrer, temperature probe, addition funnel, and condenser. The mixturewas heated to 35-40° C. in order to dissolve the starting material.Bromine (52 mL, 1.0 moles, 1.02 eq.) was added dropwise through theaddition funnel at a rate which maintained the reaction temperaturebetween 35-38° C. The mixture was then allowed to stir overnight at 35°C. The mixture was slowly cooled to −5-0° C. over two hours and thenallowed to stir at that temperature for 1 h more. The solid which formedwas then collected by filtration through a Buchner funnel and the filtercake washed with 400 mL of a cold 1:1 CH₂Cl₂:heptane solution. The graysolid was then dried in vacuo (0.2 mm Hg) at room temperature.Yield=124.3 g (63%).

Example 2 2-[(2-Formyl-4-hydroxyphenyl)methylidene]succinic acid

6-Bromo-3-hydroxybenzaldehyde, 50 g, (from Example 1) was dissolved,with stirring, in 200 mL MeOH in a 500 mL Erlenmeyer flask. Theresulting solution was filtered using a Buchner funnel lined with aglass microfibre filter. The filtered solution was charged into a 2 L3-necked round bottomed flask, equipped with an air-driven mechanicalstirrer, thermometer and reflux condenser, and stirred at roomtemperature for 2 hours. After confirmation by ¹H-NMR that the dimethylacetal is completely formed, Et₃N (111 ml) was added to the reactionflask followed by 500 mL CH₃CN. The reaction mixture was purged with N₂followed by addition of 32.5 g itaconic acid, 0.56 g Pd(OAc)₂, 2.3 gP(o-tolyl)₃ and 8.0 g Bu₄NBr. The resulting reaction mixture was heatedto reflux for 10 hours. After cooling to room temperature, about 550 mLof the reaction solvent was removed by rotary evaporation. Aqueous KOHsolution (30 g in 200 mL water) was added, with stirring, at roomtemperature. The aqueous solution was washed with 200 mL TBME and theaqueous solution was acidified to pH 1 using 200 mL 3N HCl solution. Theacidic aqueous solution was extracted with 200 mL TBME (4×). Thecombined TBME extracts were filtered through a glass microfiber linedBuchner funnel. The resulting solution was concentrated to minimumvolume by rotary evaporation. Acetonitrile (200 mL) was added and theresulting mixture was concentrated by rotary evaporation (repeated 3 or4 times). The final volume should be approx 250 mL. The heterogeneoussolution was cooled to −10° C. for 2 hours and the resulting precipitatewas filtered using a Buchner funnel and rinsed with a small amount ofcold CH₃CN. The cream-colored solid product was dried under vacuum at50° C. Yield=49.3(79%).

Example 3(S)-2-Carboxyl-4-[(2-formyldimethylacetal-4-hydroxyphenyl)]butyric acid,bis(dicyclohexylamine) salt

2-[(2-Formyl-4-hydroxyphenyl)methylidene]succinic acid (Example 2) (50g, 0.20 moles) was dissolved by heating in refluxing MeOH(450 mL) in aone liter three neck flask equipped with a condenser and an internalthermocouple. After 4 h at reflux, the solution was cooled to ambienttemperature and filtered through Whatman #1 filter paper. The filtratewas placed in a 2 L Paar bottle and DCA(84 mL, 0.42 moles, 2.1 eq.) wasadded, followed by water(50 mL), and [RuCl₂(R-BINAP)]₂-TEA(250 mg, 0.5wt %). The bottle was then placed in a Paar shaker and filled with 60psi H₂, then evacuated. This fill and evacuate sequence was repeatedtwice more. The bottle was then filled with H₂ to 60 psi a fourth timeand shaking commenced. The contents of the bottle were heated to 60° C.and the reaction monitored by ¹H NMR. After 36 h the reaction wascomplete as determined by the presence of <2%(2-[(2-formyl-4-hydroxyphenyl)methylidene]succinic acid). The contentswere allowed to cool to ambient temperature and were filtered throughWhatman #1 filter paper. The filtrate was then concentrated by rotaryevaporation to a volume of ˜200 mL. CH₃CN(500 mL) was added and themixture concentrated by rotary evaporation to ˜200 mL. This acetonitrileaddition and strip was conducted a total of three times at which pointthe mixture was allowed to stir at ambient temperature for 6 h. Thesolid was then collected on a Buchner funnel, rinsed with cold CH₃CN(100 mL) and dried in vacuo (40° C. @ 20 inches Hg). Yield=112 g (84%).

Example 4 Dimethyl (2S)-2-[(2-formyl-4-hydroxyphenyl)methyl]butanedioate

(S)-2-Carboxyl-4-[(2-formyldimethylacetal-4-hydroxyphenyl)]butyric acid,bis(dicyclohexylamine) salt (300 g, 0.453 moles) was dissolved in 1200mL of MeOH in a 3000 mL three neck flask equipped with a condenser,addition funnel, and temperature probe. Concentrated H₂SO₄(55.5 mL, 1.0moles, 2.2 equiv.) was slowly added dropwise to the stirred solution.After addition was complete, the mixture was heated to reflux and thereaction monitored by HPLC. After 19 h, the reaction was complete asobserved by HPLC. The mixture was allowed to cool to r.t. and thesolvent was removed by rotary evaporation. EtOAc(1000 mL) was added andthe solvent removed by rotary evaporation (repeated 1×) (1000 mLremoved). The precipitated DCA salts, which had formed were then removedby filtration of the mixture through Whatman #1 paper. The filter cakewas rinsed with EtOAc (200 mL). The wet cake weighed 135 grams. Thefiltrate was washed with H₂O (2×500 mL), 10 vol % H₂SO₄(1×500 mL) andsaturated aqueous NaHCO₃ (1×500 mL). The organic layer was concentratedby rotary evaporation. CH₃CN (500 mL) was added and the mixtureconcentrated (repeated 1×). A final portion of CH₃CN (400 mL) was added.The solution was then assayed for(S)-2-(2-Formyl-4-hydroxy-benzyl)-succinic acid dimethyl ester used asis. Total wt. of solution=696.2 g. Assay=15.8 wt %. Yield=110 g(86%).

Example 5[(S)-8-Hydroxy-3-oxo-2-(2,2,2-trifluoro-ethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-4-yl]-aceticacid methyl ester

A mixture of (S)-2-(2-formyl-4-hydroxy-benzyl)-succinic acid dimethylester in CH₃CN (259 g of solution, 15.4% w/w assay, 40.0 g(S)-2-(2-formylhydroxy-benzyl)-succinic acid dimethyl ester, 0.14 mol),trifluoroethylamine-HCl (23.0 g, 1.2 eq, 0.17 mol) and ZnCl₂ (9.5 g, 0.5eq, 0.07 mol) was heated to reflux for 2 hours in a 1 L round bottomflask, equipped with a Dean-Stark trap and condenser. A total of 80 mlof solvent was collected in the Dean-Stark trap.

After cooling to room temperature, a solution of 65.7 g NaBH(OAc)₃ (2.2eq, 0.31 mol) in 200 mL DMF was slowly added, with stirring. Stirringwas continued for 15 minutes at RT. The pH of the solution was adjustedto 6-6.5 by adding 400 mL saturated NaHCO₃ solution. The resultingsolution was extracted with 200 mL EtOAc (2×), the combined EtOAcextracts were filtered and concentrated. Toluene (200 ml) was added andthe resulting mixture was concentrated by rotary evaporation. Repeat.The resulting residue was dissolved in 300 mL toluene and 8 mL TFA, andresulting solution was heated to reflux for 24 hours, then cooled to RT.The reaction solution was concentrated by rotary evaporation, thendiluted with 200 mL EtOAc, washed with 200 mL saturated NaHCO₃ (2×),then concentrated to minimum volume by rotary evaporation. Toluene (200mL) was added to the residue, then 200 mL was removed from solution byrotary evaporation. Tolune (100 mL) was added, followed by removal of 50mL solvent by rotary evaporation. The resulting mixture was cooled to 0°C. for 0.5 hour and the solid material was filtered through a Buchnerfunnel and dried. The product may be dried to constant weight in avacuum oven at 60° C. Yield=34.0 g(72%).

Example 62-(2-{[tert-Butoxycarbonyl-(2,2,2-trifluoro-ethyl)-amino]-methyl}-4-methoxy-benzylidene)-succinicacid

A 1-L, 3 neck flask fitted with a thermocouple and reflux condenser wascharged with acetonitrile (240 mL, 6 volumes) and mechanical stirringbegan. The following reagents were then charged to the flask:(2-Bromo-5-methoxy-benzyl)-(2,2,2-trifluoro-ethyl)-carbamic acid butylester (40.0 g, 0.100 mol, 1.0 eq.), potassium carbonate (17.97 g, 0.130mol, 1.3 eq.), itaconic acid (15.61 g, 0.120 mol, 1.2 eq) to give awhite slurry. At this time, water (80 mL, 2 volumes) was added and thetemperature cooled upon addition as carbon dioxide was evolved. AfterCO₂ evolution ceased, the solution was degassed by placing the vesselunder vacuum for one minute and then filling with nitrogen for twominutes. This procedure was repeated 3 times leaving the solution undera nitrogen atmosphere. Palladium acetate (1.12 g, 5.0 mmol, 0.05 eq.)and tri-o-tolyl phosphine (3.04 g, 10.0 mmol, 0.10 eq.) were added in asingle portion. The degassing procedure was repeated an additional threetimes, leaving the vessel under nitrogen atmosphere. The solution washeated to reflux over 25 minutes at which time the internal temperaturereached 78° C. After 19.5 h (overnight), HPLC analysis indicated thatthe reaction was complete. The reaction was allowed to cool to roomtemperature over thirty minutes. The solution was transferred to a 1 Lflask and 220 mL of acetonitrile were removed by rotary evaporation. Theaqueous layer was transferred back to a 1 L 3-necked flask rinsing withethyl acetate (320 ml, 8 volumes) with a 60 mL addition funnel,thermocouple, pH probe (pH=6.93) and mechanical stirrer and cooled in anice bath over 30 min. The addition funnel was charged with 20 mL ofconcentrated HCl, which was added dropwise to the solution whilestirring. The internal temperature was kept below 11° C. by controllingthe rate of addition by hand. After adding 16 ml (0.192 mol, 1.92 eq) ofconcentrated HCl the pH had reached 2.83. The solution was poured into a1-L separatory funnel and was agitated. The layers were separated andthe aqueous layer was washed two additional times, at which time theaqueous layer showed no sign of product, by HPLC. The combined organicphases were filtered through Whatman quality 1 filter paper to removetrace solids and provide a clear solution. The filtrate was thenstripped to 20% of the original volume by removing 760 mL of EtOAc onthe rotary evaporator. Acetonitrile (400 mL, 10 volumes) was added andthe solution was stirred rapidly, then heated to reflux over 30 minutes.Heating was continued until solution was clear. At this point, thesolution was allowed to cool to room temperature. The resulting slurrywas cooled to 0-5° C. over 30 minutes and held at that temperature for1.5 hours. The off-white precipitate was collected on a Buchner funnel,and was dried, with heating (70° C.) in a vacuum oven for 48 h to give awhite powder 38.93 g (87 mmol, 87.0% yield).

Example 7(S)-2-(2-{[tert-Butoxycarbonyl-(2,2,2-trifluoro-ethyl)-amino]-methyl}-4-methoxy-benzyl)-succinicacid bis-dicyclohexylamine salt

2-(2-{[tert-Butoxycarbonyl-(2,2,2-trifluoro-ethyl)-amino]-methyl}-4-methoxy-benzylidene)-succinicacid (100.0 g, 0.224 mol), [RuCl₂(R-BINAP)]₂-TEA (300 mg, 0.3 wt. %),MeOH (900 mL), dicyclohexylamine (89.2 g, 0.49 mol), and H₂O (100 mL)was charged into a 2 L Parr bottle, and attached to the Parrhydrogenation apparatus. The Parr bottle was purged six times with 30psi H2. Hydrogenation was conducted, with shaking at 30-35 psi H₂, at60° C. for 20 h. The reaction mixture was cooled and concentrated invacuo. Acetonitrile was added (2 L) and reconcentrated. Freshacetonitrile (1 L) was added and the resulting mixture was stirred for 2h. The resultant solid was collected by filtration and washed with CH₃CN(100 mL). If desired, recrystallization from CH₃CN (1 L) may beperformed. The material was partitioned between 10% aq H₂SO₄ (700 mL)and EtOAc (1400 mL). The aqueous phase was washed with EtOAc (300 mL).The combined EtOAc phases were washed with H₂O (3×650 mL), 20% NaCl soln(650 mL), then dried over MgSO₄ (30 g), and concentrated in vacuo togive(S)-2-(2-{[tert-butoxycarbonyl-(2,2,2-trifluoro-ethyl)-amino]-methyl}-4-methoxy-benzyl)-succinicacid bis dicyclohexyl amine salt as a glass (78.9 g).

Example 8(S)-2-{4-Methoxy-2-[(2,2,2-trifluoro-ethylamino)-methyl]-benzyl}-succinicacid dimethyl ester

(S)-2-(2-{[tert-Butoxycarbonyl-(2,2,2-trifluoro-ethyl)-amino]-methyl}methoxy-benzyl)-succinicacid bis-dicyclohexylamine salt was dissolved in a mixture ofdichloromethane and 5.66% aq H₂SO₄. The layers were separated and theaqueous layer further extracted with dichloromethane. The combineddichloromethane layers were washed with water to pH ˜4.5. After removalof the most dichloromethane by distillation under atmospheric pressure,methanol was added, then concentrated by vacuum distillation. Freshmethanol was added, and upon cooling to ˜10° C., HCl (gas) was addedwhile maintaining temperature below 20° C. When the reaction wascomplete, the mixture was cooled to ˜10° C. and neutralized withsaturated NaHCO₃ to bring the pH to about 7, followed by vacuumdistillation to remove the most of methanol. The mixture was extractedwith toluene. The layers were separated and the toluene layer was washedwith water.

Example 9[(S)-8-Methoxy-3-oxo-2-(2,2,2-trifluoro-ethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-4-yl]-aceticacid methyl ester

A toluene solutionS)-2-{4-methoxy-2-[(2,2,2-trifluoro-ethylamino)-methyl]-benzyl}-succinicacid dimethyl ester (950 mL, 212 mmol) was placed in a 2 L round bottomflask and concentrated under rotary evaporation to a volume of 460 mL(to remove residual water). Toluene (450 mL) was added and the mixturewas transferred to a 3 neck 2 L flask. The flask was fitted with refluxcondenser, thermometer, nitrogen inlet/outlet, and stir bar. The mixturewas de-gassed under a flow of nitrogen gas. The mixture was heated to50° C. and trifluoroacetic acid (200 mmol, 22.8 g) was added over a 5min period. The mixture was heated to reflux. After 2.5 h, HPLC analysis(Waters Cosmosil 4.6×150 mm, 60% CH₃CN/40% 0.1% TFA, 220 nm, 0.5 mL/min)showed less than 0.2% (area %) of(S)-2-{4-methoxy-2-[(2,2,2-trifluoro-ethylamino)-methyl]-benzyl}-succinicacid dimethyl ester remaining. The mixture was cooled to 25° C. and waswashed with 1×400 ml NaHCO₃ solution (satd.), and 1×400 mL water. Thesolvent was removed by vacuum distillation. The residue was treated withhexane (800 ml) and was heated to reflux with rapid stirring. Thisresulted in a solution with some oily residue. Toluene (20 mL) was addedand a clear solution was obtained. The mixture was allowed to cool to25° C. with rapid stirring over a 1 hour period. The mixture was thencooled to 0-5° C. for 1 hour. The resulting solid was isolated byfiltration, washed with hexane (70 mL) and air dried to provide theproduct as an off-white solid (64.4 g, 88%).

Example 10[(S)-8-Hydroxy-3-oxo-2-(2,2,2-trifluoro-ethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-4-yl]-aceticacid methyl ester

A 5 L, 3-necked, round-bottom flask equipped with an air-drivenmechanical stirrer, was charged with methylene chloride (1530 g, 1160mL) then cooled to −5° C. in a dry ice-isopropanol bath. Borontribromide (680.7 g, 257 mL, 2.72 mol, 3.8 eq) was added at such a ratethat the temperature was maintained <2° C. The reaction was cooled to−8° C. and a solution of the non-racemic methyl ether,[(S)-8-methoxy-3-oxo-2-(2,2,2-trifluoro-ethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-4-yl]-aceticacid methyl ester (246.9 g, 0.715 mol, 1 eq) in methylene chloride (1530g, 1160 mL) was added dropwise at a temperature of −8 to −2° C. Thereaction was continued at −2° C. The reaction was deemed complete whenthe HPLC of the reaction had <0.3% of[(S)-8-methoxy-3-oxo-2-(2,2,2-trifluoro-ethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-4-yl]-aceticacid methyl ester. The reaction was then slowly transferred intomethanol (1030 g, 1303 mL, 45 eq (5.3 vol)), stirred in a 12-L 3 neckflask at −35° C., cooled with dry ice-isopropanol.

The resulting mixture was maintained at <−20° C., and treated dropwisewith saturated sodium carbonate to pH 6-7 (required approximately 2.0L(8.1 vol)). The resulting solution was transferred to a 12-L separatoryfunnel with a chloroform rinse (1.23 L) and the layers separated. Afterextraction of the aqueous layer with chloroform, the combined organiclayers were washed with 3% sodium chloride followed by brine. Theorganic layer (3.7 L) was distilled at reduced pressure to ½ volume at<35° C. and hexane (740 mL) was added at which time a precipitate waspresent. About 600 mL of solvent was distilled. The solution was cooledto 5° C. and stirred for 1 hr. The product was collected and furtherwashed with some of the cold filtrate (ca. 300 mL), and hexane (80 g,124 mL). After air drying, the product was dried at 38-40° C. at 12 mmof Hg for 15 h, to produce[(S)-8-hydroxy-3-oxo-2-(2,2,2-trifluoro-ethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-4-yl]-aceticacid methyl ester in 91.0% yield; 214.1 g (theory 236.8 g).

Example 11 2-(tert)-Butoxycarbonylamino)-6-picoline

To a 10 gallon glass-lined reactor vessel was added toluene (10.4 L),di-tert-butyldicarbonate (16.3 kg, 74.68 mol), and6-methyl-pyridin-2-ylamine (6.75 kg, 62.465 mol). The reaction vesselwas purged with nitrogen then was heated to 106.5° C. for 14 hours. Thereactor was cooled to 31° C. and the toluene was removed under vacuum.The final reactor temperature was 40.1° C. Heptane (6.7 L) was added.The resulting mixture was stirred for 15 minutes then filtered throughcelite 545 (0.67 kg) using a Sparkler filter. The reaction mixture waskept warm (35-40° C.) by applying steam to the Sparkler filter. Thefilter cake was washed with 1.5 L of heptane and the filtrate was placedback in the reactor vessel. The contents of the reactor were cooled to−21.7° C. over 1 hour and held at that temperature for 20 hours. Thesolids that formed were collected by filtration using a centrifuge. Theresulting solid was washed with cold heptane (1.5 L) and dried undervacuum for 24.5 hours to give 8.65 kg of the title product (41.59 mol,66.6% crude yield).

Example 12 1,1-Dimethylethyl methyl(6-methyl-2-pyridinyl)carbamate

A 1 L round bottom flask was charged with THF (200 mL) and sodiumhydride (60% in mineral oil, 22 g, 0.55 mol). A solution of2-(tert)-butoxycarbonylamino)-6-picoline (100 g, 99.2% PAR, 0.48 mol) inTHF (200 mL) was added over 45 minutes while maintaining temperature20-25° C. The resulting mixture was stirred for 15 minutes followed byaddition of iodomethane (102 mL, 1.64 mol) over 1 h, while maintainingtemperature 20-25° C. The resulting mixture was stirred for 3 h at roomtemperature. Deionized H₂O (100 ml) was added and the two layersseparated. The aqueous layer was extracted with hexane (150 mL). Thecombined organic layers were washed with deionized H₂O (2×100 mL) andconcentrated to provide the title product (107.6 g).

Example 13 Ethyl6-[[(1,1-dimethylethoxy)carbonyl]methylamino]-2-pyridineacetate

A 2 L 3-necked flask equipped with air driven mechanical stirrer,thermometer, addition funnel and nitrogen inlet/outlet was charged withTHF (80 mL), 1,1-dimethylethyl methyl(6-methyl-2-pyridinyl)carbamate (80g, 0.36 mol) and diethyl carbonate (157.2 mL, 1.30 mol). The flask wascooled until the internal temperature is −15° C. LDA (450 mL, 0.9 mol)was added over 1 h while maintaining temperature <−10° C. The reactionmixture was transferred to another flask which contain saturated NH₄Cl(400 mL). The two layers were separated; the aqueous layer was extractedwith ethyl acetate (2×150 mL). The organic layers were washed withdeionized H₂O (4×150 mL), combined, and concentrated to provide the tidecompound. Evaporate the solvent and weigh the product (124.7 g).

Example 14 6-(Methylamino)-2-pyridineethanol

A clean dry 2 L 3 necked flask was fitted with reflux condenser,addition funnel, stir bar, nitrogen inlet and outlet, temperaturesensor, and heating mantle. The flask was purged using a stream ofnitrogen. Lithium borohydride (4.36 g, 200 mmol) was added all at once.Tetrahydrofuran (THF, 150 mL) was charged into the addition funnel andwas added to the solid with stirring over a 10-minute period. Afterdissolution, the mixture was heated to 66° C. Ethyl6-[[(1,1-dimethylethoxy)carbonyl]methylamino]-2-pyridineacetate (110 g,374 mmol) was dissolved in THF (400 ml) and charged into the additionfunnel. The ethyl6-[[(1,1-dimethylethoxy)carbonyl]methylamino]-2-pyridineacetate solutionwas added to the LiBH₄ solution in as dropwise manner over a period of25 minutes. The addition rate was controlled so as to maintain a gentlereflux. The mixture was heated to reflux for 5 h, the heat was turnedoff, and the reaction was allowed to stir overnight at 23° C. Thereaction mixture was cooled to 10° C. and was treated with water (250mL) in a dropwise manner. The mixture was stirred for 30 min and ethylacetate (250 mL) was added. The mixture was stirred for 5 minutes andthe layers were allowed to separate. The organic layer was washed with2×250 mL saturated sodium chloride. The organic layers were stripped tothick oil in a 2 L round bottom flask. The residue was dissolved inethyl acetate (200 mL) and was extracted with 1 N HCl (2×250 mL). Theorganic layer was discarded and the acid layer was placed in a 2 L 3neck round bottom flask. The flask was heated to 50° C. for 1 h. Themixture was cooled to 10° C. and the solution was treated with 4 N NaOH(˜350 mL) to a pH of 10. The basic solution was extracted with ethylacetate (3×150 mL). Care was taken to keep the pH of the aqueous phaseabove pH=9. The ethyl acetate extracts were combined, washed with water(150 mL) and concentrated to provide the title compound as a thin yellowoil, 33.5 g, yield=58%)

Example 15S-(−)-8-[2-[6-(Methylamino)pyridin-2-yl]-1-ethoxy]-3-oxo-2-(2,2,2-trifluoroethyl)-1,2,4,5-tetrahydro-2-benzazepine-4-aceticacid

A 2.0 L 3-necked round bottomed flask, under nitrogen, was fitted withan air-driven mechanical stirrer, thermometer, and dropping funnel. To,the empty flask was charged[(S)-8-hydroxy-3-oxo-2-(2,2,2-trifluoro-ethyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-4-yl]-aceticacid methyl ester (45.5 g, 0.14 mol., 1.0 equivalent) and TBME (500 mL).To the heterogeneous[(S)-8-hydroxy-3-oxo-2-(2,2,2-trifluoro-ethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-4-yl]-aceticacid methyl ester/TBME mixture was added in one portion, a TBME solution(250 mL TBME) of 6-(methylamino)-2-pyridineethanol (25.0 g, 0.15 mol.,1.1 equivalents). To the mixture was added triphenylphosphine (39.7 g,0.15 mol., 1.1 equivalents). The heterogeneous mixture was cooled to 3°C.-5° C. To the cooled mixture was dropwise added over 13-15 minutes, asolution of diisopropylazodicarboxylate (DIAD, 30.6 g, 0.15 mol., 1.1equivalents) in TBME (60 ml). The ice-bath was removed and the reactionmixture was stirred at room temperature (18° C.-20° C.). Alternatively,the triphenylphosphine-containing reaction mixture, in toluene or TBME,may be maintained at about room temperature and the DIAD, in toluene orTBME, may be added at room temperature over a period of about 1.5 hours.In another embodiment, the triphenylphosphine-containing reactionmixture, in toluene or TBME, may be maintained at a temperature of about22° C. and the DIAD, in toluene or TBME, may be added at a temperatureof about 22° C. over a period of about 1.5 hours.

After 3 hours, the mixture was concentrated by rotary evaporation toone-third of its original volume(˜500 mL TBME removed). The mixture wascooled to 0° C.-2° C. for 30 minutes. The mixture was filtered throughqualitative filter paper. The filtrate was extracted with 3 N NaOH(100mL). The layers were separated and the organic layer was extracted withbrine(100 mL). To the mixture was added in one portion, an aqueoussolution (125 mL H₂O) of lithium hydroxide monohydrate (11.4 g, 0.27mol., 2.2 equivalents). The mixture was heated at 50° C.-55° C. Afterabout 30 minutes to 1 hour, the mixture was cooled to room temperature,and diluted with H₂O (375 mL). The layers were separated and the aqueouslayer was extracted with fresh TBME (250 mL). The layers were separated.To the aqueous layer was added methanol (125 mL). The aqueous methanolicmixture was acidified with concentrated HCl (10-12 mL) until pH=6.7. Themixture was seeded with authenticS-(−)-8-[2-[6-(methylamino)pyridin-2-yl]-1-ethoxy]-3-oxo-2-(2,2,2-trifluoroethyl)-1,2,4,5-tetrahydro-2-benzazepine-4-aceticacid. The mixture was further acidified with concentrated HCl (10-12 mL)until pH=5.2(S-(−)-8-[2-[6-(methylamino)pyridin-2-yl]-1-ethoxy]-3-oxo-2-(2,2,2-trifluoroethyl)-1,2,4,5-tetrahydro-2-benzazepine-4-aceticacid starts to precipitate at pH=6.4). The mixture was cooled to 0°C.-2° C. for 30 minutes. The precipitatedS-(−)-8-[2-[6-(methylamino)pyridin-2-yl]-1-ethoxy]-3-oxo-2-(2,2,2-trifluoroethyl)-1,2,4,5-tetrahydro-2-benzazepine-4-aceticacid was collected by filtration and dried for 15 minutes. The crudeS-(−)-8-[2-[6-(methylamino)pyridin-2-yl]-1-ethoxy]-3-oxo-2-(2,2,2-trifluoroethyl)-1,2,4,5-tetrahydro-2-benzazepine-4-aceticacid precipitate was dissolved in hot methanol (450 mL), filteredthrough qualitative filter paper, seeded with authentic material, andallowed to stand at room temperature for 16 hours. The recrystallizedtitle compound was collected by filtration and dried for 15 minutes. Therecrsytallized title compound,[(S)-8-[2-(6-methylamino-pyridin-2-yl)-ethoxy]-3-oxo-2-(2,2,2-trifluoro-ethyl)-2,3,4,5-tetrahydro-1-H-benzo[c]azepin-4-yl]-aceticacid, was taken up in water (165 mL) and heated at 65° C.-70° C. for 30minutes. The mixture was cooled to room temperature and the slurriedmaterial was collected by filtration. The title compound was oven driedin-vacuo (65° C.-70° C., 1.0 mm Hg) to constant weight(2-4 hours). Thedried title compound was isolated in 56% yield, and assayed (HPLC) at98.3%.

Example 16 2-(3-Hydroxypropyl)aminopyridine-N-oxide

A mixture of 2-chloro-pyridine-N-oxide (one molar equivalent),3-amino-1-propanol (about 2 molar equivalents), and sodium bicarbonate(about 2 molar equivalents) was heated to about 90° C. in t-amyl alcoholuntil HPLC analysis indicates <3% area 2-chloro-pyridine-N-oxide.Additional 3-amino-1-propanol may be added to complete the reaction. Themixture is cooled to about 25-32° C. and is treated with a 4:1(v/v)mixture of ethyl acetate:methanol. The mixture was filtered and thefilter cake was rinsed with additional 4:1(v/v) ethyl acetate:methanol.The combined filtrates were concentrated by distillation, and methanoland ethyl acetate were added. The mixture was cooled to about 50-60° C.and filtered. Methanol was added to the filtrate, followed by hexane.The mixture was allowed to cool and seed crystals of3-(1-oxy-pyridin-2-ylamino)-propan-1-ol were added during the coolingprocess. The product was isolated by filtration, rinsing the filter cakewith cold hexane and drying.

Representative HPLC conditions: Column: YMC ODS-aq, C18 S, 5 μ; 4.6×250mm; Mobile phase: 10:90 acetonitrile:water with 0.1% trifluoroaceticacid, Flow rate: 0.9 mL/m; Detection: UV, 255 nm, Injection volume: 20μL, Temperature: ambient

Example 17 N-(3-Bromopropyl)-2-pyridinamine-1-oxide hydrogenbromide

A solution 3-(1-Oxy-pyridin-2-ylamino)-propan-1-ol (one molarequivalent) in methylene chloride was treated with thionyl bromide(about 1.2 molar equivalents) while maintaining the temperature belowabout 25° C. The resulting solution was stirred until HPLC analysisindicates <2% area 3-(1-oxy-pyridin-2-ylamino)-propan-1-ol. The mixturewas filtered and the filter cake was rinsed with methylene chloride. Thefiltrates were concentrated by atmospheric distillation and methylt-butyl ether was added to the warm solution. Additional solvent wasdistilled and the mixture was allowed to cool to about 20-25° C. Methylt-butyl ether was added and the mixture was cooled to about 0-5° C. Themixture was filtered and the filter cake was rinsed with methyl t-butylether and dried.

Representative HPLC conditions: Column: Zorbax SB-C18; 4.6 mm×7.5 cm,Mobile Phase: 30:70 acetonitrile: water, Flow rate: 1 mL/min, Detection:UV, 240 nm, Injection volume: 5 μL, Temperature: ambient

All solvents and reagents are accepted on vendor specifications, and maybe checked for identity by spectroscopic or chromatographic comparisonwith authentic samples. Unless indicated otherwise, raw materials aretypically ≧95% pure as purchased from the supplier.

The above description fully discloses how to make and use the presentinvention. However, the present invention is not limited to theparticular embodiments described hereinabove, but includes allmodifications thereof within the scope of the following claims. Thevarious references to journals, patents and other publications which arecited herein comprises the state of the art and are incorporated hereinby reference as though fully set forth.

1. A process for preparing a compound of Formula (I):

from a benzazepine-phenol of Formula (II):

wherein the benzazepine-phenol of Formula (II) is prepared by a processcomprising converting a compound of Formula (III):

to a compound of Formula (IV):

wherein: R^(P) is H or a suitable phenol protecting group; R³ and R⁴ arethe same or different and are each independently H or a carboxylic acidester protecting group; R² is R⁷, C₁-C₄ alkyl, C₁-C₄ haloalkyl, A-C₀-C₄alkyl-, A-C₂-C₄ alkenyl-, A-C₂-C₄ alkynyl-, A-C₃-C₄ oxoalkenyl-, A-C₃-C₄oxoalkynyl-, A-C₀-C₄ aminoalkyl-, A-C₃-C₄ aminoalkenyl-, A-C₃-C₄aminoalkynyl-, optionally substituted by any accessible combination ofone or more R¹⁰ R⁷; A is H, C₃-C₆ cycloalkyl, Het or Ar; R⁷ is —COR⁸,COCR′₂R⁹, —C(S)R⁸, —S(O)_(m)OR′, —S(O)_(m)NR′R″, —PO(OR′), —PO(OR′)₂,—NO₂, or tetrazolyl; each R⁸ independently is —OR′, —NR′R″, —NR′SO₂R′,—NR′OR′, or —OCR′₂CO(O)R′; R⁹ is —OR′, —CN, —S(O)_(r)R′, —S(O)_(m)NR′₂,—C(O)R′, C(O)NR′₂, or —CO₂R′; R¹⁰ is H, halo, —OR¹¹, —CN, —NR′R¹¹, —NO₂,—CF₃, CF₃S(O)_(r)—, —CO ₂R′, —CONR′₂, A-C₀-C₆ alkyl-, A-C₁-C₆ oxoalkyl-,A-C₂-C₆ alkenyl-, A-C₂-C₆ alkynyl-, A-C₀-C ₆ alkyloxy-, A-C₀-C₆alkylamino—or A-C₀-C₆ a1kyl-S(O)_(r)-; R¹¹ is R′, C(O)R′, —C(O)NR′₂,—C(O)OR′, —S(O)_(m)R′, or —S(O)_(m)NR′₂; R¹ is

W is —(CHR^(g))_(a)—U—(CHR^(g))_(b)—; U is absent or CO, CR^(g) ₂,C(═CR^(g) ₂), S(O)_(k), O, NR^(g), CR^(g)OR^(g), CR^(g)(OR^(k))CR^(g) ₂, CR^(g) ₂CR^(g)(OR^(k)), C(O)CR₂, CR^(g) ₂C(O), CONR^(i), NR^(i)CO,OC(O), C(O)O, C(S)O, OC(S), C(S)NR^(g), NR^(g)C(S), S(O)₂NR^(g),NR^(g)S(O)₂ N═N, NR^(g)NR^(g), NR^(g)CR^(g) ₂, CR^(g) ₂NR⁵, CR^(g) ₂0OCR^(g) ₂, C≡C or CR^(g)═CR^(g); G is NR^(e), S or O; R^(g) is H, C₁-C₆alkyl, Het-C₀-C₆ alkyl, C₃-C₇ cycloalkyl-C₀-C₆ alkyl or Ar—C₀-C₆ alkyl;R^(k) is R^(g), —C(O)R^(g), or —C(O)OR^(f); R^(i) is H, C₁-C₆ alkyl,Het-C₀-C₆ alkyl, C₃-C₇ cycloalkyl-C₀-C₆ alkyl, Ar—C₀-C₆ alkyl, or C₁-C₆alkyl substituted by one to three groups chosen from halogen, CN, NR^(g)₂, OR^(g), SR^(g), CO₂R^(g), and CON(R^(g))₂; R^(f) is H, C₁-C₆ alkyl orAr—C₀-C₆ alkyl; R^(e) is H, C₁-C₆ alkyl, Ar—C₀-C₆ alkyl, Het-C₀-C₆alkyl, C₃-C₇ cycloalkyl-C ₀-C₆ alkyl, or (CH₂) _(k)CO₂R^(g); R^(b) andR^(c) are independently selected from H, C₁-C₆ alkyl, Ar—C₀-C₆ alkyl,Het-C₀-C₆ alkyl, or C₃-C₆ cycloalkyl-C₀-C₆ alkyl, halogen, CF₃, OR^(f),S(O)_(k)R^(f), COR^(f), NO₂, N(R^(f))₂, CO(NR^(f))₂, CH₂N(R^(f))₂, orR^(b) and R^(c) are joined together to form a five or six memberedaromatic or non-aromatic carbocyclic or heterocyclic ring, optionallysubstituted by up to three substituents chosen from halogen, CF₃, C₁-C₄alkyl, OR^(f), S(O)_(k)R^(f), COR^(f), CO₂R^(f), OH, NO₂, N(R^(f))₂,CO(NR^(f))₂, and CH₂N(R^((Rf))₂; or methylenedioxy; R^(b) and R^(c) areindependently selected from H, C₁-C₆ alkyl, Ar—C₀-C₆ alkyl, Het-C₀-C₆alkyl, or C₃-C₆ cycloalkyl-C₀-C₆ alkyl, halogen, CF₃, OR^(f),S(O)_(k)R^(f), COR^(f), NO₂, N(R^(f))₂, CO(NR^(f))₂, CH₂N(R^(f))₂, orR^(b) and R^(c) are joined together to form a five or six memberedaromatic or non-aromatic carbocyclic or heterocyclic ring, optionallysubstituted by up to three substituents chosen from halogen, CF₃, C₁-C₄alkyl, OR^(f), S(O)_(k)R^(f), COR^(f), CO₂R^(f), OH, NO₂, N(R^(f))₂,CO(NR^(f))₂, and CH₂N(R^((Rf))₂; or methylenedioxy; Q¹, Q², Q³ and Q⁴are independently N or C—R^(y), provided that no more than one of Q¹,Q², Q³ and Q⁴ is N; R′ is H, C₁-C₆ alkyl, Ar—C₀-C₆ alkyl or C₃-C₆cycloalkyl-C₀-C₆ alkyl; R″ is R′, —C(O)R′ or —C(O)OR′; R′″ is H, C₁-C₆alkyl, Ar—C₀-C₆ alkyl, Het-C₀-C₆ alkyl, or C₃-C₆ cycloalkyl-C₀-C₆ alkyl,halogen, CF₃, OR^(f), S(O)_(k)R^(f), COR^(f), NO₂, N(R^(f))₂,CO(NR^(f))₂, CH₂N(R^(f))₂; R^(y) is H, halo, —OR^(g), —SR^(g), —CN,—NR^(g)R^(k), —NO₂, —CF₃, CF₃S(O)_(r)—, —CO₂R^(g), —COR^(g) or —CONR^(g)₂, or C₁-C₆ alkyl optionally substituted by halo, —OR^(g), —SR^(g), —CN,—NR^(g)R″, —NO₂, —CF₃, R′S(O)_(r)—, —CO₂R^(g), —COR^(g) or —CONR^(g) ₂;a is 0, 1 or 2; b is 0, 1 or 2; k is 0, 1 or 2; m is 1 or 2; r is 0, 1or 2; s is 0, 1 or 2; u is 0 or 1; and v is 0 or 1; or apharmaceutically acceptable salt thereof.
 2. A process according toclaim 1, comprising preparing a compound of Formula (I-S):

from a benzazepine-phenol of Formula (II-S):

wherein the benzazepine-phenol of Formula (II-S) is prepared by aprocess comprising converting a compound of Formula (III):

to a compound of Formula (IV-S):


3. A process according to claim 1, further comprising a process forpreparing the compound of Formula (II) comprising the steps of: 1)treating a compound having Formula (a)

wherein R^(P) is H or a suitable phenol protecting group and X ishalogen, —OSO₂F, or —OSO₂CF₃, with a compound having the formula:

to form a compound of Formula (b)

2) converting the compound of Formula (b) to a compound of Formula (c);

wherein R⁵ and R^(5′) are C₁-C₄ alkyl or R⁵ and R^(5′), taken togetherwith the atoms to which they are attached form a saturated 5- or6-membered heterocyclic ring and Z and Z′ are independently selectedfrom O, NH or NCH₃; 3) converting the compound of Formula (c) to acompound of Formula (d):

4) converting the compound of Formula (d) to a compound of Formula (e)

5) converting the compound of Formula (e) to a compound of Formula (f)

6) converting the compound of Formula (f) to a compound of Formula (II).4. A process according to claim 1, further comprising a process forpreparing the compound of Formula (II) comprising the steps of: 1)converting 3-hydroxybenzaldehyde to a compound of Formula (aa)

2) treating the compound of Formula (aa) with itaconic acid to form acompound of Formula (bb):

3) converting the compound of Formula (bb) to a compound of Formula (cc)

where R⁵ and R^(5′) are C₁-C₄ alkyl or R⁵ and R^(5′), taken togetherwith the atoms to which they are attached form a saturated 5- or6-membered heterocyclic ring; 4) converting the compound of Formula (cc)to a compound of Formula (dd)

5) converting the compound of Formula (dd) to a compound of Formula (ee)

6) converting the compound of Formula (ee) to a compound of Formula(II).
 5. A process according to claim 2, further comprising a processfor preparing the compound of Formula (II-S) comprising the steps of: 1)converting the compound having the formula:

wherein R⁵ and R^(5′) are C₁-C₄ alkyl or R⁵ and R^(5′), taken togetherwith the atoms to which they are attached form a saturated 5- or6-membered heterocyclic ring and Z and Z′ are independently selectedfrom O, NH or NCH₃, to a compound having the formula:

2) converting the compound formed in step 1) into a compound having theformula:

3) converting the compound formed in step 2) into the compound havingthe formula:

4) converting the compound formed in step 3) into the compound ofFormula (II-S).
 6. A process according to claim 2, further comprising aprocess for preparing the compound of Formula (II-S) comprising thesteps of: 1) converting the compound having the formula:

wherein R⁵ and R^(5′) are C₁-C₄ alkyl or R⁵ and R^(5′), taken togetherwith the atoms to which they are attached form a saturated 5- or6-membered heterocyclic ring, into a compound having the formula:

2) converting the compound formed in step 1) into a compound having theformula:

3) converting the compound formed in step 2) into the compound ofFormula (II-S).
 7. A process according to claim 1, further comprising aprocess for preparing the compound of Formula (I) having the formula:

comprising the steps of: 1) converting 2-amino-6-methylpyridine into acompound having the formula:

wherein R^(P) is a suitable amino protecting group; 2) converting thecompound formed in step 1) to a compound having the formula:

3) converting the compound formed in step 2) to a compound having theformula:

wherein R⁶ is H or an alkyl carboxylic acid ester protecting group; 4)converting the compound formed in step 3) to a compound having theformula:

5) treating the compound formed in step 4) with a compound having theformula:

to form a compound having the formula:

6) converting the compound formed in step 5) to the compound of FormulaI.
 8. A process according to claim 1, further comprising a process forpreparing the compound of Formula (I) having the formula:

comprising the steps of: 1) converting 2-amino-6-methylpyridine into acompound having the Formula:

2) converting the compound formed in step 1) to a compound having theformula:

3) converting the compound formed in step 2) to a compound having theformula:

4) converting the compound formed in step 3) to a compound having theformula:

5) treating the compound formed in step 4) with a compound having theformula:

to form a compound having the formula:

6) converting the compound formed in step 5) to the compound of Formula(I).
 9. A process according to claim 1, further comprising a process forpreparing the compound of Formula (I) having the formula:

comprising the steps of: 1) converting a compound having the formula:

wherein X is halogen or —OSO₂CF₃, to a compound having the formula:

2) converting the compound formed in step 1) into a compound having theformula:

wherein X′ is halogen, —OSO₂CH₃, —OSO₂CF₃, —OSO₂(phenyl), or—OSO₂(p-tolyl); 3) treating the compound formed in step 2) with acompound having the formula:

to form a compound having the formula:

4) converting the compound formed in step 3) into the compound ofFormula (I).
 10. A process according to claim 1, further comprising aprocess for preparing the compound of Formula (I) having the formula:

comprising the steps of: 1) converting 2-chloropyrdine, N-oxide to acompound having the formula:

2) converting the compound formed in step 1) into a compound having theformula:

3) treating the compound formed in step 2) with a compound having theformula:

to form a compound having the formula:

4) converting the compound formed in step 3) into the compound ofFormula (I).
 11. A process according to claim 1, wherein R³ is H, C₁-C₆alkyl or phenyl-C₁-C₄ alkyl-, wherein the phenyl moiety is unsubstitutedor substituted by one or more substituents selected from ortho and parasubstituents selected from chloro, bromo, nitro, methoxy and methyl andR⁴ is H, C₁-C₆ alkyl or phenyl-C₁-C₄ alkyl-, wherein the phenyl moietyis unsubstituted or substituted by one or more substituents selectedfrom ortho and para substituents selected from chloro, bromo, nitro,methoxy and methyl.
 12. A process according to claim 1, wherein R⁴ is Hor C₁-C₄ alkyl and R³ is H or C₁-C₄ alkyl.
 13. A process according toclaim 1, wherein R⁴ is H and R³ is methyl.
 14. A compound having theformula:

wherein: R^(P) is H or a suitable phenol protecting group; R⁴ is H or acarboxylic acid ester protecting group; R⁵ and R^(5′) are C₁-C₄ alkyl orR⁵ and R^(5′), taken together with the atoms to which they are attachedform a saturated 5- or 6-membered heterocyclic ring and Z and Z′ areindependently selected from O, NH or NCH₃; or a pharmaceuticallyacceptable salt or solvate thereof.
 15. A compound according to claim14, wherein R⁴ is H, C₁-C₆ alkyl or phenyl-C₁-C₄ alkyl-, wherein thephenyl moiety is unsubstituted or substituted by one or moresubstituents selected from ortho and para substituents selected fromchloro, bromo, nitro, methoxy and methyl.
 16. A compound according toclaim 14, wherein R⁴ is H, R^(P) is H, Z and Z′ are both O, and R⁵ andR^(5′) are methyl.
 17. A compound having the formula:

wherein: R^(P) is H or a suitable phenol protecting group; R³ is H or acarboxylic acid ester protecting group; or a pharmaceutically acceptablesalt or solvate thereof.
 18. A compound according to claim 17, whereinR³ is H, C₁-C₆ alkyl or phenyl-C₁-C₄ alkyl-, wherein the phenyl moietyis unsubstituted or substituted by one or more substituents selectedfrom ortho and para substituents selected from chloro, bromo, nitro,methoxy and methyl.
 19. A compound according to claim 17, wherein R^(P)is H and R³ is H or C₁-C₄ alkyl.
 20. A compound:2-[(2-formyl-4-hydroxyphenyl)methylidene]succinic acid,2-carboxyl-4-[(2-formyldimethylacetal-4-hydroxyphenyl)]butyric acid,bis(dicyclohexylamine) salt,(S)-2-carboxyl-4-[(2-formyldimethylacetal-4-hydroxyphenyl)]butyric acid,bis(dicyclohexylamine)salt, dimethyl2-[(2-formyl-4-hydroxyphenyl)methyl]butanedioate, anddimethyl(2S)-2-[(2-formyl-4-hydroxyphenyl)methyl]butanedioate.